Elevated Na/H exchanger 1 (SLC9A1) emerges as a marker for tumorigenesis and prognosis in gliomas.
Elevated Na/H exchanger 1 (SLC9A1) emerges as a marker for tumorigenesis and prognosis in gliomas.
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DOI：
10.1186/s13046-018-0923-z
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发表时间：
2018-10-17
期刊：
影响因子：
--
通讯作者：
Jia W
中科院分区：
文献类型：
--
作者：
Guan X;Luo L;Begum G;Kohanbash G;Song Q;Rao A;Amankulor N;Sun B;Sun D;Jia W
人类SLC9A1基因（溶质载体家族9A1）编码的钠/氢交换器1 （NHE1）是维持胶质瘤细胞内碱性pH （pHi）和Warburg效应的主要H+外排机制。然而，到目前为止，还没有临床研究探索NHE1蛋白在癌症治疗中的药理抑制作用。在这项研究中，我们研究了NHE1在胶质瘤中的表达及其与胶质瘤临床预后的关系。本研究分析了包含325个胶质瘤样本转录组测序数据的中国胶质瘤基因组图谱（CGGA）和包含698个胶质瘤mRNAseq数据的癌症基因组图谱（TCGA）。建立C57BL/6 J小鼠颅内同基因胶质瘤模型SB28和GL26，研究NHE1蛋白表达及其抑制剂HOE642抑制对肿瘤发生和抗pd1治疗的影响。通过免疫荧光染色和流式细胞术分析评估肿瘤血管生成、免疫原性和进展。分析SLC9A1 mRNA在CGGA和TCGA两个数据集中的表达，发现SLC9A1 mRNA在高级别胶质瘤中表达水平显著升高。SLC9A1 mRNA在异柠檬酸脱氢酶（IDH）1/2野生型胶质母细胞瘤（GBM）和间充质胶质瘤亚型中表达尤其丰富。胶质瘤中SLC9A1 mRNA水平升高与生存几率降低有关。潜在的机制包括促进血管生成和细胞外基质重塑。SLC9A1 mRNA表达的增加也与肿瘤相关的巨噬细胞积累有关。在小鼠胶质瘤模型中，NHE1抑制剂HOE642可减少胶质瘤体积、侵袭并延长总生存期。阻断NHE1蛋白还通过激活CD8 t细胞积累，增加干扰素γ (Ifng)的表达，刺激免疫原性肿瘤微环境，并使动物对抗pd -1治疗敏感。我们的研究结果强烈表明，NHE1蛋白是胶质瘤发生和预后的一个标志。阻断NHE1蛋白是辅助抗癌治疗的新策略。本文的在线版本（10.1186/s13046-018-0923-z）包含补充资料，授权用户可使用。
Sodium/hydrogen exchanger 1 (NHE1), encoded by the SLC9A1 gene (SoLute Carrier family 9A1) in humans, is the main H+ efflux mechanism in maintaining alkaline intracellular pH (pHi) and Warburg effects in glioma. However, to date, there are no clinical studies exploring pharmacological inhibition of NHE1 protein in cancer treatment. In this study, we investigated NHE1 expression in gliomas and its relationship with glioma clinical outcome. The Chinese Glioma Genome Atlas (CGGA) dataset containing transcriptome sequencing data of 325 glioma samples and the Cancer Genome Atlas (TCGA) with 698 glioma mRNAseq data were analyzed in this study. Mouse SB28 and GL26 intracranial syngeneic glioma models in C57BL/6 J mice were established to investigate NHE1 expression and impact of NHE1 protein inhibition with its inhibitor HOE642 on tumorigenesis and anti-PD1 therapy. Tumor angiogenesis, immunogenicity, and progression were assessed by immunofluorescence staining and flow cytometric profiling. Analysis of SLC9A1 mRNA expression in two data sets, CGGA and TCGA, reveals significantly higher SLC9A1 mRNA levels in higher grade gliomas. The SLC9A1 mRNA expression was especially enriched in isocitrate dehydrogenase (IDH)1/2 wild-type glioblastoma (GBM) and in mesenchymal glioma subtypes. Worsened survival probabilities were correlated with the elevated SLC9A1 mRNA levels in gliomas. The underlying mechanisms include promoting angiogenesis, and extracellular matrix remodeling. Increased SLC9A1 mRNA expression was also associated with tumor-associated macrophage accumulation. NHE1 inhibitor HOE642 reduced glioma volume, invasion, and prolonged overall survival in mouse glioma models. Blockade of NHE1 protein also stimulated immunogenic tumor microenvironment via activating CD8 T-cell accumulation, increasing expression of interferon-gamma (Ifng), and sensitized animals to anti-PD-1 therapy. Our findings strongly suggest that NHE1 protein emerges as a marker for tumorigenesis and prognosis in glioma. Blocking NHE1 protein is a novel strategy for adjuvant anti-cancer therapies. The online version of this article (10.1186/s13046-018-0923-z) contains supplementary material, which is available to authorized users.
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影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
CGCG 成人弥漫性胶质瘤治疗临床实践指南。
影响因子：
9.7
作者：
Jiang, Tao;Mao, Ying;Wang, Qixue
通讯作者：
Wang, Qixue
影响因子：
4.1
作者：
Cong D;Zhu W;Kuo JS;Hu S;Sun D
通讯作者：
Sun D
影响因子：
6.7
作者：
Leng, Tiandong;Shi, Yejie;Xiong, Zhi-Gang;Sun, Dandan
通讯作者：
Sun, Dandan
DOI：
10.1186/s13046-017-0642-x
发表时间：
2017-11-28
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Abbruzzese C;Matteoni S;Signore M;Cardone L;Nath K;Glickson JD;Paggi MG
通讯作者：
Paggi MG